Contact hypersensitivity (CHS) is an important cause of skin disease and is a delayed-type hypersensitivity response to hapten that is a two part process. CHS begins with sensitization to the hapten following initial exposure. Subsequent immune response leads to a vigorous response. Although CHS was previously thought to be mediated mainly by T cells, recent studies have demonstrated that natural killer (NK) cells are capable of mediating a CHS response in the absence of T, NKT or B cells. Prior work in the applicant's laboratory recently showed that during NK cell maturation, NK cells become functionally competent (licensed) through interactions between inhibitory Ly49 receptors and self-MHC class I molecules. As a result of licensing, NK cells can be activated through their activation receptors. The applicant has now found that NK cells are activated in the draining lymph node during the CHS response in a manner that requires D2m expression, suggesting that the activation of NK cells requires licensing or another MHC-I dependent effect. Attempts to better characterize these NK cells also revealed that MyD88 is required to mount a vigorous CHS response but not to activate the NK cells. The observation that MyD88 is required for the CHS response suggests that a Toll-like receptor, IL-1 and/or IL-18 is required since these molecules signal through MyD88. The central hypothesis of this application is that the innate immune system plays a vital role in the CHS response through NK cells and MyD88. The goal of this proposal is to test this hypothesis via three specific aims: 1) Determine the characteristics of the NK cells from the draining lymph node, 2) determine the mechanism of NK cell activation in the draining lymph node, 3) characterize the defect in contact hypersensitivity in the MyD88 deficient mice. Together, these studies will lead to insight into the role of NK cells and innate immunity in CHS. Contact hypersensitivity (CHS) is an important cause of skin disease and Natural Killer (NK) cells have recently been shown to play a role. Insight into the contribution of NK cells in CHS should result in the development of novel NK cell based therapies.